tbuckley/cabot-search huggingface dataset:
Abstract 6338: Higher-resolution protein interaction networks for precision medicine: A case for drug repurposing in head and neck cancer
Authors: Maryam Shah, Arsalan Riaz, Faisal Khan
Journal: Cancer Research (2022)

Abstract Protein-Protein Interaction (PPI) networks can be useful scaffolds for the integration of whole cell multi-omics datasets that can aid significantly in drug discovery research. This study aims to use domain-domain interaction (DDI) data to produce high resolution protein interaction networks with enhanced topological insights for head and neck squamous cell carcinoma as well as the more well studies, triple negative breast cancer (TNBC). An extensive literature review identified 65 driver genes for HNSCC and 19 genes for TNBC which collectively had 557 and 316 protein domains. Eventually, 343/557 and 191/316 domains had well-annotated somatic mutations reported in COSMIC. PPI networks were created using BioGrid and STRING data and the top two hubs in PPI networks were TP53 for HNSCC and EGFR for TNBC, while the top two hubs in DDI networks were PF12796 (NOTCH) and PF07714 (EGFR) for HNSCC and TNBC networks, respectively. The top nodes in the densest sub-clusters based on module analysis in PPI networks were ERBB4, MET and NOTCH1 for HNSCC, and FGFR1, AR, and EGFR for TNBC. For DDI networks, the top nodes in the densest subcluster for HNSCC were PF06816 (NOTCH1-3), while for TNBC PF07714 domains from FGFR1, ERBB2 and EGFR were the top nodes. Our preliminary results re-emphasize the significance of NOTCH, EGFR and TP53, and their domains, in cancer networks. Next, we attempted to decipher potential candidates for drug repurposing and were able to map 20 out of the 31 FDA approved cancer drugs against proteins within our HNSCC network. EGFR was revealed as a hub gene in both HNSCC and TNBC networks with most of the therapies designed against the PF07714 kinase domain of EGFR. PF07714 is also a common domain in ERBB4, EPHA2, MAP2K1 and MET, and was targeted by different drugs in other cancer types. Next, we attempt to undertake an in vitro drug screen of all candidates against HNSCC cell lines to validate our in silico findings. Citation Format: Maryam Shah, Arsalan Riaz, Faisal Khan. Higher-resolution protein interaction networks for precision medicine: A case for drug repurposing in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6338.
Reply
Authors: Hiroki Murai, Takahiro Kodama, Tetsuo Takehara
Journal: Hepatology (2022)

We thank Dr. Jiang et al. for their interest in our manuscript. We would like to respond to their comments as the order appeared in their letter. First, regarding the sampling method, we sampled avoiding necrotic and blood components in the tumor and confirmed the integrity of the obtained DNA and RNA as described in Materials and Methods,[1] as well as pathology of the tumor site. On the other hand, we agree that high intratumor heterogeneity is a characteristic of hepatocellular carcinoma (HCC), and thus, different sampling sites in the same tumor may yield different results, which is always a limitation even in the cancer genome atlast project.[2] Second, regarding the definition of steatotic HCC, we applied histological criteria for its diagnosis among 113 patients with nonviral HCC. Steatotic HCC was diagnosed by the presence of lipid droplets in more than 5% of tumor cells in HE staining as described in the supplementary methods.[1] We only used chemical shift magnetic resonance imaging to diagnose steatotic HCC among 30 patients with advanced HCC. It has been already reported that fat fraction measured by chemical shift imaging (FFCSI) correlates strongly with histological lipid deposition in the liver, unless there is significant iron deposition.[3] Taken together with our own assessment, we believe that FFCSI is a reliable method to assess the lipid deposition. Lastly, we agree with the limitation such that our study has a retrospective, nonrandomized, and relatively smaller cohort, as well as limited information about genomic abnormality. Nevertheless, we belive that the association between intratumor steatosis and exhausted tumor immune microenvironment is novel and clinically important, and we thus hope that its clinical significane will be validated in a larger prospective cohort. CONFLICT OF INTEREST Nothing to report.
Epidemiological cut-off value and antibiotic susceptibility test methods for azithromycin in a collection of multi-country invasive non-typhoidal Salmonella
Authors: Bieke Tack, Marie-France Phoba, Phe Thong, Palpouguini Lompo, Charlien Hupko, Stefanie Desmet, Delphine Martiny, Wesley Mattheus, Maria Pardos de la Gandara, Lisette Mbuyi-Kalonji, Laura Kuijpers, Benoit Prevost, Barbara Barbé, Olivier Vandenberg, Octavie Lunguya, Joaquim Ruiz, Jan Jacobs, Liselotte Hardy
Journal: Clinical Microbiology and Infection (2022)

ObjectiveAzithromycin is an alternative to treat invasive non-typhoidal Salmonella (iNTS) infections. We determined its epidemiological cut-off (ECOFF) and compared azithromycin susceptibility testing methods for iNTS.MethodsWe used EUCAST ECOFFinder to determine the minimum inhibitory concentrations (MIC; obtained by broth microdilution) ECOFF and corresponding disk zone diameters of 515 iNTS from blood cultures in Democratic Republic of Congo, Burkina Faso, Rwanda, and Cambodia. Transferable resistance mechanisms were determined by polymerase chain reaction. We compared azithromycin susceptibility testing by semi-automated broth microdilution (customized Sensititre panel; reference), agar dilution, gradient tests (bioMérieux, Liofilchem, HiMedia; read at 80% (MIC80%) and 100% inhibition (MIC100%)), and disk diffusion (Rosco, Oxoid, BD, Liofilchem) for 161 wild- and 198 non–wild-type iNTS.ResultsAzithromycin MIC ECOFF was 16 mg/L corresponding to a 12 mm zone diameter; mphA was detected in 192/197 non–wild- and 0/47 wild-type iNTS. Categorical agreement was excellent (≥98%) for all methods. Essential agreement was very good for agar dilution (>90%) but moderate for gradient tests (MIC80%: 52% to 71% and MIC100%: 72% to 91%). Repeatability was good for all methods/brands. Interreader agreement was high for broth microdilution and agar dilution (all ≤1 twofold dilution difference) and disk diffusion (>96% ≤3 mm difference) but lower for gradient tests (MIC80% & MIC100%: 83% to 94% ≤1 twofold dilution difference).DiscussionAzithromycin ECOFF of iNTS was 16 mg/L, i.e. equal to Salmonella Typhi. Disk diffusion is an accurate, precise, and user-friendly alternative for agar dilution and broth microdilution. Reading gradient tests at 100% instead of 80% inhibition improved accuracy and precision.
Abstract 6334: <i>In vivo</i> efficacy and toxicity of a reduced potency DNA guanine mono-alkylating ADC payload suitable for the treatment of solid tumors
Authors: Paul J. Jackson, Paolo Andriollo, Nicolas Veillard, George Procopiou, David E. Thurston
Journal: Cancer Research (2022)

Abstract Antibody-Drug Conjugates (ADCs) are a growing class of therapeutic agents for the treatment of cancer, with thirteen approved and over 100 others in clinical development. The pyridinobenzodiazepine (PDD) platform is a toolbox of sequence-selective, DNA Guanine mono-alkylating ADC payloads with varying potencies and biophysical properties, enabling a payload-based approach to targeting solid tumours and haematological malignancies. We recently reported the development of a lower potency DNA mono-alkylator, FGX20-75, with substantially superior in vivo properties to other DNA alkylating agents and an efficacy/tolerability profile on-par with a topoisomerase inhibitor-based ADC. This molecule is active in the low nanomolar range (i.e., median potency of 6 nM across a 15 cell-line screen), but is sufficiently hydrophilic to allow efficient conjugation to IgG antibodies with Drug Antobody Ratios (DARs) of up to 7. A maleimide-linked analogue of FGX20-75 has been conjugated to a number of antibodies with a DAR of 4. The ADCs produced exhibit significant in vivo efficacy in human tumour xenograft models. For example, in one case, an ADC targeted to an undisclosed antigen produced complete tumour regressions at 10 mg/kg dosing (Q7dx2) in patient-derived xenograft model of osteosarcoma. A substantially increased tolerability profile compared to other DNA-interactive payloads has been observed (e.g., single dose MED of &amp;lt; 1 mg/kg and MTD in mice of up to 80 mg/kg for a DAR 4 construct). Furthermore, in cynomolgus toxicity studies, a HNSTD has yet to be established at 8 mg/kg. Thus, the increase in loading compared to other DNA-interactive payloads compensates for the drop in potency of FGX20-75, resulting in a potent ADC with substantially increased tolerability and potent efficacy in solid tumours. The favourable hydrophobicity profile of the low potency alkylator FGX20-75, and its ease of conjugation to antibodies, along with the significant in vivo efficacy and tolerability of the ADCs produced from it, suggest that this low potency DNA-alkylating payload represents a promising new approach in the treatment of solid tumours. Citation Format: Paul J. Jackson, Paolo Andriollo, Nicolas Veillard, George Procopiou, David E. Thurston. In vivo efficacy and toxicity of a reduced potency DNA guanine mono-alkylating ADC payload suitable for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6334.
Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer
Authors: Aya Shiba-Ishii, Ted W. Johnson, Ibiayi Dagogo-Jack, Mari Mino-Kenudson, Theodore R. Johnson, Ping Wei, Scott L. Weinrich, Michele A. McTigue, Makeba A. Walcott, Linh Nguyen-Phuong, Kristin Dionne, Adam Acker, Lesli A. Kiedrowski, Andrew Do, Jennifer L. Peterson, Jaimie L. Barth, Beow Y. Yeap, Justin F. Gainor, Jessica J. Lin, Satoshi Yoda, Aaron N. Hata
Journal: Nature Cancer (2022)
EULAR/PRES recommendations for vaccination of paediatric patients with autoimmune inflammatory rheumatic diseases: update 2021
Authors: Marc H A Jansen, Christien Rondaan, Geertje E Legger, Kirsten Minden, Yosef Uziel, Natasa Toplak, Despoina Maritsi, Lotte van den Berg, Guy A M Berbers, Patricia Bruijning, Yona Egert, Christophe Normand, Marc Bijl, Helen E Foster, Isabelle Koné-Paut, Carine Wouters, Angelo Ravelli, Ori Elkayam, Nicolaas M Wulffraat, Marloes W Heijstek
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Recent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations. Methods Recommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement. Results In general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles–mumps–rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients. Conclusions These recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.
FRK inhibits glioblastoma progression via phosphorylating YAP and inducing its ubiquitylation and degradation by Siah1
Authors: Yan Wang, Kai Wang, Jiale Fu, Yu Zhang, Yufei Mao, Xu Wang, Xiang Wang, Rutong Yu, Xiuping Zhou
Journal: Neuro-Oncology (2022)

We previously report that yes-associated protein (YAP), the core downstream effector of Hippo pathway, promotes the malignant progression of glioblastoma (GBM). However, although classical regulatory mechanisms of YAP are well explored, how YAP is modulated by the Hippo-independent manner remains poorly understood. Meanwhile, the nonreceptor tyrosine kinase Fyn-related kinase (FRK), which exhibits low expression and possesses tumor suppressor effects in GBM, is reported to be involved in regulation of protein phosphorylation. Here, we examined whether FRK could impede tumor progression by modulating YAP activities.Human GBM cells and intracranial GBM model were used to assess the effects of FRK and YAP on the malignant biological behaviors of GBM. Immunoblotting and immunohistochemistry were used to detect the expression of core proteins in GBM tissues. Co-immunoprecipitation, proximity ligation assay, luciferase assay and ubiquitination assay were utilized to determine the protein-protein interactions and related molecular mechanisms.The expression levels of FRK and YAP were inversely correlated with each other in glioma tissues. In addition, FRK promoted the ubiquitination and degradation of YAP, leading to tumor suppression in vitro and in vivo. Mechanistically, FRK interacted with and phosphorylated YAP on Tyr391/407/444, which recruited the classical E3 ubiquitin ligase Siah1 to catalyze ubiquitination and eventually degradation of YAP. Siah1 is required for YAP destabilization initiated by FRK.We identify a novel mechanism by which FRK orchestrates tumor-suppression effect through phosphorylating YAP and inducing its ubiquitination by Siah1. FRK-Siah1-YAP signaling axis may serve as a potential therapeutic target for GBM treatment.
“RB-reactivator screening” as a novel cell-based assay for discoveries of molecular targeting agents including the first-in-class MEK inhibitor trametinib (trade name: Mekinist)
Authors: Toshiyuki Sakai
Journal: Pharmacology & Therapeutics (2022)

The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.
Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction
Authors: Kentaro Sugano, Stuart Jon Spechler, Emad M El-Omar, Kenneth E L McColl, Kaiyo Takubo, Takuji Gotoda, Mitsuhiro Fujishiro, Katsunori Iijima, Haruhiro Inoue, Takashi Kawai, Yoshikazu Kinoshita, Hiroto Miwa, Ken-ichi Mukaisho, Kazunari Murakami, Yasuyuki Seto, Hisao Tajiri, Shobna Bhatia, Myung-Gyu Choi, Rebecca C Fitzgerald, Kwong Ming Fock, Khean-Lee Goh, Khek Yu Ho, Varocha Mahachai, Maria O'Donovan, Robert Odze, Richard Peek, Massimo Rugge, Prateek Sharma, Jose D Sollano, Michael Vieth, Justin Wu, Ming-Shiang Wu, Duowu Zou, Michio Kaminishi, Peter Malfertheiner
Journal: Gut (2022)

An international meeting was organised to develop consensus on (1) the landmarks to define the gastro-oesophageal junction (GOJ), (2) the occurrence and pathophysiological significance of the cardiac gland, (3) the definition of the gastro-oesophageal junctional zone (GOJZ) and (4) the causes of inflammation, metaplasia and neoplasia occurring in the GOJZ.
Hepatic events associated with sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes: a nationwide cohort study
Authors: Sungho Bea, Han Eol Jeong, Sohee Park, Oriana H Y Yu, Yoosoo Chang, Juhee Cho, Dong Hyun Sinn, Young Min Cho, Ju-Young Shin
Journal: Gut (2022)
Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade
Authors: Michal Harel, Coren Lahav, Eyal Jacob, Nili Dahan, Itamar Sela, Yehonatan Elon, Shani Raveh Shoval, Galit Yahalom, Iris Kamer, Alona Zer, Ofer Sharon, David P Carbone, Adam P Dicker, Jair Bar, Yuval Shaked
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Immune checkpoint inhibitors (ICIs) have revolutionized the cancer therapy landscape due to long-term benefits in patients with advanced metastatic disease. However, robust predictive biomarkers for response are still lacking and treatment resistance is not fully understood. Methods We profiled approximately 800 pre-treatment and on-treatment plasma proteins from 143 ICI-treated patients with non-small cell lung cancer (NSCLC) using ELISA-based arrays. Different clinical parameters were collected from the patients including specific mutations, smoking habits, and body mass index, among others. Machine learning algorithms were used to identify a predictive signature for response. Bioinformatics tools were used for the identification of patient subtypes and analysis of differentially expressed proteins and pathways in each response group. Results We identified a predictive signature for response to treatment comprizing two proteins (CXCL8 and CXCL10) and two clinical parameters (age and sex). Bioinformatic analysis of the proteomic profiles identified three distinct patient clusters that correlated with multiple parameters such as response, sex and TNM (tumors, nodes, and metastasis) staging. Patients who did not benefit from ICI therapy exhibited significantly higher plasma levels of several proteins on-treatment, and enrichment in neutrophil-related proteins. Conclusions Our study reveals potential biomarkers in blood plasma for predicting response to ICI therapy in patients with NSCLC and sheds light on mechanisms underlying therapy resistance.
Fasting Substrate Concentrations Predict Cardiovascular Outcomes in the CANagliflozin cardioVascular Assessment Study (CANVAS)
Authors: Ele Ferrannini, Simona Baldi, Tiziana Scozzaro, Vasilis Tsimihodimos, Fisseha Tesfaye, Wayne Shaw, Norman Rosenthal, Gemma A. Figtree, Bruce Neal, Kenneth W. Mahaffey, Vlado Perkovic, Michael K. Hansen
Journal: Diabetes Care (2022)

To examine whether the circulating substrate mix may be related to the incidence of heart failure (HF) and cardiovascular (CV) mortality and how it is altered by canagliflozin treatment.We measured fasting glucose, free fatty acids (FFA), glycerol, β-hydroxybutyrate, acetoacetate, lactate, and pyruvate concentrations in 3,581 samples from the CANagliflozin cardioVascular Assessment Study (CANVAS) trial at baseline and at 1 and 2 years after randomization. Results were analyzed by univariate and multivariate Cox proportional hazards models.Patients in the lowest baseline FFA tertile were more often men with a longer duration of type 2 diabetes (T2D), higher urinary albumin excretion, lower HDL-cholesterol levels, higher history of CV disease (CVD), and higher use of statins and insulin. When all seven metabolites were used as predictors, FFA were inversely associated with incident hospitalized HF (hazard ratio [HR] 0.33 [95% CI 0.21-0.55]), while glycerol was a positive predictor (2.21 [1.45-3.35]). In a model further adjusted for 16 potential confounders, including prior HF and CVD and pharmacologic therapies, FFA remained a significant negative predictor. FFA and glycerol also predicted CV mortality (HR 0.53 [95% CI 0.35-0.81] and 1.81 [1.26-2.58], respectively) and all-cause death (0.50 [0.36-0.70] and 1.64 [1.22-2.18]). When added to these models, background insulin therapy was an independent positive predictor of risk of death. Canagliflozin treatment significantly increased plasma FFA and β-hydroxybutyrate regardless of background antihyperglycemic therapy.A constitutive metabolic setup consisting of higher lipolysis may be beneficial in delaying or preventing hospitalized HF; a further stimulation of lipolysis by canagliflozin may reinforce this influence.